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HETE and HPETE biosynthesis and metabolism


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HETE and HPETE biosynthesis and metabolism

HETE and HPETE biosynthesis and metabolism

Besides Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase andcyclooxygenase) ( COX-1) and Prostaglandin-endoperoxide synthase 2 (prostaglandinG/H synthase and cyclooxygenase) ( COX-2) that catalyze the first step ofArachidonic acid metabolic pathway leading to prostaglandin formation, there isanother family of lipoxygenase enzymes in mammalian cells that catalyze the conversion ofArachidonic acid to hydroperoxyeicosatetraenoic acids (HPETEs) that can be furtherenzymatically reduced to the hydroxylated form (HETE).

Arachidonic acid is converted to 12(R)-HPETE by Arachidonate12-lipoxygenase, 12R type ( ALOX12B ) [1], [2] and to12(S)-HPETE by Arachidonate 12-lipoxygenase, 12S type ( ALOX12 ) [3], [4]. Both 12(R)-HPETE and 12(S)-HPETE further may bereduced to 12(R)-HETE and 12(S)-HETE, respectively, by Glutathioneperoxidase 1 ( GPX1 ) [5], [2] or by Glutathioneperoxidase 4 (phospholipid hydroperoxidase) ( GPX4 (PHGPx) ) [5].12(S)-HETE can be further oxidized to 12(S),20-DihydroxyETE (12(S),20-diHETE ) by specific cytochrome P450 enzyme, isoforms leukotriene-B420-monooxygenase: Cytochrome P450, family 4, subfamily F, polypeptide 2 ( CYP4F2)[6] and Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3) [7], [8].

Arachidonate 5-lipoxygenase ( ALOX5 ) converts Arachidonic acid to5(S)-HPETE [9], [10], [11] that is furtherreduced to 5(S)-HETE by Microsomal glutathione S-transferases 2 and 3 (MGST2 and MGST3) accordingly [12]. CYP4F2 [6] and CYP4F3 [13], [8] oxidize 5(S)-HETE to5(S),20-DihydroxyETE ( 5(S),20-diHETE ).

5(S),12(S)-DihydroperoxyETE ( 5(S),12(S)-diHPETE ) is formed from either12(S)-HPETE or 5(S)-HPETE by action of ALOX5 [14] orArachidonate 15-lipoxygenase ( ALOX15) [15], respectively.

ALOX15 [16], [17], [18], [19] andArachidonate 15-lipoxygenase, type B ( ALOX15B ) [20] convert15(S)-HydroperoxyETE ( 15(S)-HPETE ) to Arachidonic acid. GPX1 canreduce 15(S)-HPETE to hydroxyl form 15(S)-HETE [21].ALOX5 converts 15(S)-HPETE to 5(S),15(S)-DihydroperoxyETE (5(S),15(S)-DiHPETE ) [22], [23], [19]. Moreover,ALOX15 can convert 5(S)-HPETE to the same product 5(S),15(S)-diHPETE[24] that can be further reduced to 5(S),15(S)-DihydroxyETE (5(S),15(S)-diHETE ) by GPX1 [25].

ALOX12 converts 15(S)-HPETE to 8(S),15(S)-DihydroperoxyETE (8(S),15(S)-diHPETE ) [26], [27],14(R),15(S)-DihydroperoxyETE ( 14(R),15(S)-diHPETE ) [26], [27], or 14,15-Leukotriene A4 ( 14,15-LTA4 ) [27], [28].Same double oxygenation products were identified for recombinant ALOX15 [18]. 14,15-LTA4 is hydrolyzed to 14(R),15(S)-DihydroxyETE (14(R),15(S)-DiHETE ) by Epoxide hydrolase 2, cytoplasmic ( EPHX2 ) [29].

Thromboxane A synthase 1 (platelet) ( THAS ) and Prostaglandin I2(prostacyclin) synthase ( PTGIS ) convert 15(S)-HPETE to 15-OxoETE[30].

Arachidonic acid can be oxidized to active metabolites by certain specificcytochrome P450 enzymes (CYPs). 19-HydroxyETE ( 19-HETE ) and 20-HydroxyETE (20-HETE ) are formed by Cytochrome P450, family 2, subfamily J, polypeptide 2 (CYP2J2) [31], Cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) [32], Cytochrome P450, family 4, subfamily A, polypeptide 11 (CYP4A11 ) [33], CYP4F2 [33] or CYP4F3 [34], respectively.

CYP2J2 metabolizes Arachidonic acid to Epoxyeicosatrienoic acids (EETs):5,6-EET, 8,9-EET, 11,12-EET and 14,15-EET [35],[31]. CYP2C9 and CYP2C8 also was shown to catalyze formation of11,12-EET and 14,15-EET. EETs are rapidly metabolized via soluble epoxidehydrolase EPHX2 to corresponding dihydroxyeicosatrienoic acids (DHETs):8,9-DHET, 11,12-DHET and 14,15-DHET [36], [37].